Hypoxemia/tissue hypoxia (H) has long been associated with procoagulant events, especially venous thrombosis, a major cause of morbidity and mortality. Experimental limb immobilization leads to a rapid fall in blood oxygen tension in parallel with fibrin deposition in venous valve pockets, thereby providing a nidus for thrombus formation. In a model of normobaric hypoxia, we have provided the first outline of a pathway through which oxygen deprivation triggers coagulation: hypoxia upregulates tissue factor and plasminogen activator inhibitor (PAI)-1 in mononuclear phagocytes (MPs), ultimately causing vascular fibrin deposition. We hypothesize that there are two pivotal and unexpected events in this H-triggered pathway, both of which are independent of hypoxia-inducible factor (HIF)-1: activation of protein kinase C isoform betaII (PKCbetaII) and activation of the transcription factor Egr-1. Tissue factor induction in hypoxic MPs is due to increased transcription at Egr-1 sites in the promoter, and Egr-1 null mice subject to oxygen deprivation display absence of tissue factor induction and vascular fibrin deposition. Our in vitro studies have traced the H-associated pathway culminating in Egr-1 transcription back to PKCbetaII: hypoxia activates PKCbetaII, the latter triggers a raf- and MEK-dependent pathway activating MAP kinases and Elk-1; and, activated Elk-1, in concert with Serum Response Factor, induces transcription of Egr-1. Our underlying concept is that events occurring at the earliest stage of oxygen deprivation, PKCbetaII and Egr-1 activation (each seen within minutes of H), are critical to the formation of thrombogenic foci within hypoxemic vasculature. Our first aim is to evaluate the role of PKCbeta in H-associated vascular fibrin formation using PKCbeta O mice, and to extend our concept of H-induced vascular perturbation to a model of lung ischemia by analyzing the response of PKCbeta O and Egr-10 mice. Our second aim addresses the hypothesis that activation of PKCbetaII in MPs is a key event driving the procoagulant mechanism, as well as other pathways contributing to ischemic tissue injury, by making and analyzing transgenic mice with targeted suppression or activation of PKCbetaII in Mps. Our overall goal is to determine if PKCbetaII and Egr-1 are potential therapeutic targets for preserving vascular homeostasis in response to hypoxemic and ischemic stress.